One of the biggest impediments to the successful treatment of cocaine addiction is the high rate of relapse, following even extended periods of drug abstinence. For this reason, understanding the mechanisms that contribute to craving and relapse is of consummate importance for our ability to provide adequate pharmacotherapies for drug abuse. Complicating the problem are the many different kinds of stimuli that have been shown to elicit a reinstatement of drug-taking behavior. For this reason, the proposed project attempts to identify the neural substrates contributing to the relapse in cocaine self-administration following presentation of cocaine itself, environmental cues previously predictive of cocaine, or stress. In order to accomplish this goal, rats trained to self-administer intravenous cocaine will undergo behavioral extinction and then be tested for their propensity to recommence drug-taking behavior following exposure to cocaine, cocaine-paired cues or stress. In some of the proposed experiments, subjects will have one of several target limbic structures (the VTA, BLA dPFC or vPFG) reversibly inactivated with tetrodotoxin prior to reinstatement testing. In others, glutamate and dopamine levels in the NAC following presentation of each of the three reinstatement primes will be determined using microdialysis procedures. Taken together, these experiments should identify the contribution of 1) the VTA, BLA dPFC or vPFG, and 2) the accumbal projections of these areas, to cocaine-, stress- and environmentally-induced relapse.